RESUMEN

Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and ß-carboline alkaloid harmine against cancer cell lines and Plasmodium falciparum. The hybrids were prepared from the corresponding amines by 1,1'-carbonyldiimidazole (CDI)-mediated synthesis. In vitro evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine 16 as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 (IC 50 = 5.48 ± 3.35 µmol L-1). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the Plasmodium life cycle identified CQ-based UT harmiquine 12 as a novel antiplasmodial hit because it displayed low IC 50 values in the submicromolar range against CQ-sensitive and resistant strains (IC 50 0.06 ± 0.01, and 0.19 ± 0.02 µmol L-1, respectively), and exhibited high selectivity against Plasmodium, compared to mammalian cells (SI = 92).

Asunto(s)

RESUMEN

Artemisinin is a component part of current frontline medicines for the treatment of malaria. The aim of this study is to make analogues of artemisinin using microbial transformation and evaluate their in vitro antimalarial activity. A panel of microorganisms were screened for biotransformation of artemisinin (1). The biotransformation products were extracted, purified and isolated using silica gel column chromatography and semi-preparative HPLC. Spectroscopic methods including LC-HRMS, GC-MS, FT-IR, 1D and 2D NMR were used to elucidate the structure of the artemisinin metabolites.1H NMR spectroscopy was further used to study the time-course biotransformation. The antiplasmodial activity (IC50) of the biotransformation products of 1 against intraerythrocytic cultures of Plasmodium falciparum were determined using bioluminescence assays. A filamentous fungus Aspergillus niger CICC 2487 was found to possess the best efficiency to convert artemisinin (1) to a novel derivative, 4-methoxy-9,10-dimethyloctahydrofuro-(3,2-i)-isochromen-11(4H)-one (2) via ring rearrangement and further degradation, along with three known derivatives, compound (3), deoxyartemisinin (4) and 3-hydroxy-deoxyartemisinin (5). Kinetic study of the biotransformation of artemisinin indicated the formation of artemisinin G as a key intermediate which could be hydrolyzed and methylated to form the new compound 2. Our study shows that the anti-plasmodial potency of compounds 2, 3, 4 and 5 were ablated compared to 1, which attributed to the loss of the unique peroxide bridge in artemisinin (1). This is the first report of microbial degradation and ring rearrangement of artemisinin with subsequent hydrolysis and methoxylation by A.niger. KEY POINTS: • Aspergillus niger CICC 2487 was found to be efficient for biotransformation of artemisinin • A novel and unusual artemisinin derivative was isolated and elucidated • The peroxide bridge in artemisinin is crucial for its high antimalarial potency • The pathway of biotransformation involves the formation of artemisinin G as a key intermediate.

Asunto(s)

RESUMEN

A library of 1H-1,2,3-triazole-tethered 4-aminoquinoline-benzoxaborole hybrids as well as aryl substituted benzoxaborole analogues was synthesized and screened for their anti-plasmodial efficacy against both chloroquine-susceptibility 3D7 and chloroquine-resistant W2 strains of P. falciparum. The inclusion of quinoline core among the synthesized analogues resulted in substantial enhancement of anti-plasmodial activities. Further, the spacer of a flexible alkyl chain is marginally preferred over piperazyl-ethyl in inhibiting growth of P. falciparum. The most potent 4-aminoquinoline-benzoxaborole conjugate with ethyl as spacer exhibited IC50 values of 4.15 and 3.78 µM against 3D7 CQ-susceptible and W2 CQ-resistant strains of P. falciparum with lower cross resistance with Chloroquine. There was no difference in anti-plasmodial activities between the CQ-susceptible 3D7 and CQ-resistant W2 strains of P. falciparum for the benzoxaborole derivatives lacking a quinoline core.

Asunto(s)

RESUMEN

Putranjivah (Putranjiva roxburghii Wall, family - Putranjivaceae) is an Indian native medicinal plant used to treat many diseases such as treatment of mouth and stomach ulcers, hot swellings, smallpox, burning sensation and ophthalmopathy. The study of chemical constituents in the bark of P. roxburghii resulted in a new triterpene (6) along with five known triterpenoids (1-5). The chemical characterisation was based on 1H, 13C, 2D-NMR experimentation, and ESI-MS data. The anti-plasmodial activity was investigated by measuring parasite-specific lactate dehydrogenase (pLDH) based in vitro assay. The IC50 value results showed that friedlein (2.40 ± 0.70) and roxburghonol (4.10 ± 1.7 µg/ml) possess better anti-plasmodial activity than other isolated triterpenes (2-5) but not as potent as chloroquine (0.023 ± 0.002 µg/ml) against chloroquine-sensitive Plasmodium falciparum (3D7) strain.

Asunto(s)

RESUMEN

BACKGROUND: Resistance of Plasmodium falciparum against common anti-malarial drugs emphasizes the need of alternative and more effective drugs. Synthetic derivatives of 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine have showed in vitro anti-plasmodial activities. The present study aimed to evaluate the molecular binding and anti-plasmodial activity of synthetic compounds in vivo. METHODS: The molecular docking was used to study the binding of compounds to haem and Plasmodium falciparum lactate dehydrogenase (PfLDH). Acute toxicity of the synthetic compounds was evaluated based on the modified up & down method. The anti-plasmodial activity of the compounds was conducted by the two standard tests of Peters' and of Rane, using chloroquine-sensitive Plasmodium berghei in mice. Also, the toxicity to the internal organs of mice was evaluated on the seventh day after the treatment in addition to the histopathology of their liver. Compound 3 that showed high activity in the lowest dose was selected for further pharmacodynamic studies. RESULTS: According to the docking studies, the active site of PfLDH had at least four common residues, including Ala98, Ile54, Gly29, and Tyr97 to bind the compounds with the affinity, ranging from - 8.0 to - 8.4 kcal/mol. The binding mode of ligands to haem revealed an effective binding affinity, ranging from - 5.1 to - 5.5 kcal/mol. Compound 2 showed the highest  % suppression of parasitaemia (99.09%) at the dose of 125 mg/kg/day in Peters' test. Compound 3, with 79.42% suppression, was the best in Rane's test at the lowest dose (31 mg/kg/day). Compound 3 was confirmed by the pharmacodynamic study to have faster initial parasite elimination in the lowest concentration. The histopathology of the livers of mice did not reveal any focal necrosis of hepatocytes in the studied compounds. CONCLUSIONS: The docking studies verified Pf LDH inhibition and the inhibitory effect on the haemozoin formation for the studied compounds. Accordingly, some compounds may provide new avenues for the development of anti-malarial drugs without liver toxicity, although further studies are required to optimize their anti-plasmodial activity.

Asunto(s)

RESUMEN

The present paper describes the synthesis, anti-plasmodial, and cytotoxic evaluation of 7-chloroquinoline-based conjugates with isatins/indoles/ nitroimidazoles, obtained via Cu-promoted 1,3-dipolar cycloadditions. On contemplating SAR of the synthesized series, the inclusion of indole and nitroimidazole-core improved the anti-plasmodial activities while the isatin seemed to have a lesser effect. The conjugate with a nitroimidazole-core and hexyl chain length as a spacer between the two pharmacophores was found to be most potent among the synthesized series and displayed an IC50 of 0.12 µM and a selectivity index of 1748.

Asunto(s)

RESUMEN

Bromodomain-containing proteins (BDPs) are involved in the regulation of eukaryotic gene expression. Compounds that bind and/or inhibit BDPs are of interest as tools to better understand epigenetic regulation, and as possible drug leads for different diseases, including malaria. In this study, we assessed the activity of 42 compounds demonstrated or predicted (using virtual screening of a pharmacophore model) to bind/inhibit eukaryotic BDPs for activity against Plasmodium falciparum malaria parasites. In silico docking studies indicated that all compounds are predicted to participate in a typical hydrogen bond interaction with the conserved asparagine (Asn1436) of the P. falciparum histone acetyltransferase (PfGCN5) bromodomain and a conserved water molecule. Only one compound (the dimethylisoxazole SGC-CBP30; a selective inhibitor of CREBBP (CBP) and EP300 bromodomains) is also predicted to have a salt-bridge between the morpholine nitrogen and Glu1389. When tested for in vitro activity against asynchronous asexual stage P. falciparum Dd2 parasites, all compounds displayed 50% growth inhibitory concentrations (IC50) >10 µM. Further testing of the three most potent compounds using synchronous parasites for 72 h showed that SGC-CBP30 was the most active (IC50 3.2 µM). In vitro cytotoxicity assays showed that SGC-CBP30 has ∼7-fold better selectivity for the parasites versus a human cell line (HEK 293). Together these data provide a possible starting point for future investigation of these, or related compounds, as tools to understand epigenetic regulation or as potential new drug leads.

Asunto(s)

RESUMEN

Epoxyazadiradione (1), a major compound derived from Neem oil, showed modest anti-plasmodial activity against CQ-resistant and CQ-sensitive strains of the most virulent human malaria parasite P. falciparum. A series of analogues were synthesized by modification of the key structural moieties of this high yield natural product. Out of the library of all compounds tested, compounds 3c and 3g have showed modest anti-plasmodial activity against CQ-sensitive (IC50 2.8 ± 0.29 µM and 1.5 ± 0.01 µM) and CQ-resistant strains (IC50 1.3 ± 1.08 µM and 1.2 ± 0.14), while compounds 3k, 3l and 3m showed modest activity against CQ-sensitive strain of P. falciparum with IC50 values of 2.3 ± 0.4 µM, 2.9 ± 0.1 µM and 1.7 ± 0.06 µM, respectively. Additionally, cytotoxic properties of these derivatives against SIHA, PANC 1, MDA-MB-231, and IMR-3 cancer cell lines were also studied and the results indicated that low cytotoxic potentials of all the derivatives which indicating the high selectivity index of the compounds.

Asunto(s)

RESUMEN

Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors. Aiming to obtain HDAC inhibitors with potent and preferential anti-plasmodial activity, we synthesized a mini-library of alkoxyamide-based HDAC inhibitors containing hydrogen bond acceptors in the cap group. Using a 5-step synthetic route, 12 new inhibitors were synthesized and assayed against Plasmodium falciparum asexual blood stage parasites (clones 3D7 and Dd2) and human cells (HepG2). The most active compound 6h (Pf3D7 IC50 : 0.07 µM; PfDd2 IC50 : 0.07 µM) was 25-fold more toxic against the parasite versus human HepG2 cells. Selected compounds were shown to cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs.

Asunto(s)

RESUMEN

Introducción: Argemone mexicana L. y Parthenium hysterophorus L. son plantas con antecedentes de uso contra la malaria en Cuba. Varios estudios avalan la actividad antiplasmodial de estas especies en otros países. Alcaloides y lactonas son los principios activos de estas plantas.Objetivo: evaluar la actividad antiplasmodial de extractos enriquecidos en alcaloides y en lactonas de A. mexicana y de P. hysterophorus colectadas en Cuba.Métodos: se prepararon extractos crudos de la parte aérea de A. mexicana y de la raíz de P. hysterophorus; un extracto enriquecido en alcaloides de A. mexicana; así como enriquecidos en lactonas de raíz y parte aérea de P. hysterophorus. La actividad de los extractos se evaluó in vitro frente a P. berghei y se determinó su citotoxicidad frente a fibroblastos humanos MRC-5. El extracto más selectivo se evaluó in vivo en un modelo de malaria de roedores.Resultados: solamente las fracciones sin alcaloides y sin lactonas no presentaro acción inhibitoria del desarrollo de la esquizogonia de P. berghei a 100 mg/mL. El extracto enriquecido en lactonas de la parte aérea de P. hysterophorus fue el más citotóxico y menos selectivo (IS< 1). El resto de los extractos activos presentaron índices de selectividad similares (3,0; 3,7 y 3,1). La administración intraperitoneal del extracto crudo de A. mexicana causó la reducción significativa de la parasitemia en los ratones tratados con 500 mg/kg, mientras el enriquecido en alcaloides provocó toxicidad a 200 mg/kg y no produjo reducción significativa de la parasitemia a 100 mg/kg y 150 mg/kg...

Introduction: Argemone mexicana L. and Parthenium hysterophorus L. are plants with history of antimalarial use in Cuba. Several studies have validated the antiplasmodial activity of these species in other countries. Alkaloids and lactones are the active principles of these plants.Objective: to evaluate antiplasmodial activity of alkaloid-rich and lactone-rich extracts from A. mexicana and P. hysterophorus harvested in Cuba.Methods: Crude extracts from the aerial parts of A. mexicana and from the root of P. Hysterophorus; alkaloid- rich extract from A. mexicana and two lactone-rich extracts from root and aerial part of P. Hysterophorus were prepared. The activity of these extracts was evaluated in vitro against P. berghei and citotoxicity against human fibroblast MRC-5 was determined. The most selective extract was evaluated in vivo in a rodent model.Results: Only those fractions without alkaloids and without lactones exhibited non inhibitory action on P. berghei squizogony development at 100 g/mL. The lactone- rich extract of P. hysterophorus aerial part was the most cytotoxic but the least selective (IS< 1). The rest of active extracts exhibited similar selectivity indexes (3.0; 3.7 y 3.1). Intraperitoneal administration of A. mexicana crude extract caused significant reduction of parasitemia in the mice treated with 500 mg/kg, whereas, alkaloid- rich extract caused toxicity at 200 mg/kg and caused a non-significant reduction of parasitemia at 100 mg/kg and 150 mg/kg. The treatment with crude extract of P. hysterophorus root was very toxic at a dose of 500 mg/kg, whereas the lactone-rich extract was no toxic and brought a significant reduction of parasitemia in mice treated with 1 000 mg/kg.Conclusions: The results show the potential of lactone-rich extract from P. hysterophorus root as a basis for a future anti-malarial phytomedicine(AU)

Asunto(s)

Asunto(s)

RESUMEN

A series of substituted 3-azabicyclo[4.1.0]hept-4-ene derivatives were prepared and analysed by cyclic voltammetry. Preparative aerobic electrochemical oxidation reactions were then carried out. Three original endoperoxides were isolated, characterised and subjected to antimalarial and cytotoxicity activity assays.

RESUMEN

A 26-member library of novel N-hydroxyquinolinone derivatives was synthesized by a one-pot Buchwald-type palladium catalyzed amidation and condensation sequence. The design of these rare scaffolds was inspired from N-hydroxypyridones and 2-quinolinones classes of compounds which have been shown to have rich biological activities. The synthesized compounds were evaluated for their anti-plasmodial and anti-bacterial properties. In addition, these compounds were screened for their iron(II)-chelation properties. Notably, four of these compounds exhibited anti-plasmodial activities comparable to that of the natural product cordypyridone B.

Asunto(s)

RESUMEN

A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine.

Asunto(s)

RESUMEN

Two bisbenzylisoquinoline and one hasubanane alkaloids: (-)-pseudocurine (1), (-)-pseudoisocurine (2) and (-)-10-oxoaknadinine (3), were isolated from leaf extract of Stephania abyssinica, a plant used in traditional medicine in South Nyanza region of Kenya. They were characterized using 1D ((1)H, (13)C and DEPT) and 2D (COSY, NOESY, HMQC and HMBC) NMR techniques. (-)-Pseudocurine (1) and (-)-pseudoisocurine (2) exhibited strong to moderate anti-plasmodial activity while (-)-10-oxoaknadinine (3) showed moderate to mild activity.

Asunto(s)

RESUMEN

In the search of active principles from the stem bark of Entandrophragma angolense, we submitted the compounds isolated from the dichloromethane-methanol (1:1) extract of the stem bark to antimalarial test against chloroquine resistant strain W2 of Plasmodium falciparum malaria parasite. Only 7alpha-obacunyl acetate and a cycloartane derivative exhibited a good activity, with IC(50)s of 2 and 5.4 microg/ml respectively. Other compounds were moderately active.